Establishing the novel ex-vivo focal demyelination model of Multiple Sclerosis in other laboratories to reduce and replace live animal use.

在其他实验室建立新型多发性硬化症离体局灶性脱髓鞘模型，以减少和替代活体动物的使用。

• 批准号: NC/W000989/1
• 负责人: Ben Newland
• 金额: $ 9.5万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FW000989%2F1
• 关键词: Establishing; novel; ex; vivo; focal

Current therapies for treating multiple sclerosis (MS) patients are inadequate for managing progressive MS, so new therapies are needed. The central nervous system of MS patients has some areas that seem relatively unaffected (the neuronal fibres retain their insulating sheath called myelin), whereas other areas are damaged (the myelin is lost, compromising neuronal function and health). This is a dynamic situation, whereby the body continually repairs the damage, but ultimately fails with disease progression. Much research aims to enhance remyelination (repairing the myelin sheath) as a key area for new therapeutic intervention, thus protecting the health and function of the neurons. However, to test new remyelination based therapies, laboratory animals must be used to model MS, and these models are costly, often don't faithfully replicate the "patchy" nature of the human disease, and shed limited light on how the therapy worked.We have recently made a better laboratory model of MS, that allows this patchy nature of MS demyelination to be recapitulated in a dish, without using live animals in the process. Researchers can now, for the first time, study the complex interplay between the "healthy" and "damaged" tissue in a dish. This advancement means that new remyelination therapies can be tested faster, more effectively, with better understanding of how they are working, and greatly reduces the number of animals required.Where previously one live adult animal would give one experimental result for one region of their nervous system (i.e., either the brain or spinal cord), our new model uses slices of euthanised newborn mouse brain or spinal cord cultured in dishes and analysed separately. This gives researchers six brain slices AND 10 spinal cord slices - all from a single animal. Where 100s of lab animals would be used for a single therapeutic test, now the tissue of a few animals can be used instead, with the added benefit of better understanding how the therapy works too. It is also important to mention that previously an experimental animal may have had to experience suffering during the interventions required to create the MS condition, whereas no intervention is carried out on a live animal with this new model that we have developed, thus replacing the use of live animals.Having seen the power of this model to increase scientific value and reduce the use of animals, we are now keen to transfer these skills and knowledge to other research groups working on MS. Dr. Dombrowski and Prof. Fitzgerald, both running independent research groups at Queen's University Belfast, approached us to use this model in their laboratories. This grant has three aims. Firstly, to finance a researcher to bring the skills and knowledge associated with the new MS model to the Belfast laboratories. The primary aim is to reduce the number of animals needed in their research, by replacing their existing live animal models with our new model. Secondly, we aim to encourage widespread adoption of this model throughout the UK, Europe and elsewhere, by making training videos and detailed protocols freely available online, thus leading to better MS research capabilities with lower animal use. Lastly, we will optimise the production of the materials required to make this new MS model, so that it can easily be rolled out to large number of laboratories in a simple, cost-effective and reproducible manner. We foresee that the immediate and tangible benefits that this new model of MS will bring to researchers will be a major attraction driving them to adopt it. These include reduced costs (live animal experiments are costly), the ability to work on multiple nervous system regions concomitantly and gaining better insight into how the therapeutic is working. This grant is required to catalyse and drive this adoption, spreading the knowledge and protocols required for this model, reducing animal use worldwide.

目前治疗多发性硬化症患者的方法不足以治疗进展性多发性硬化症，因此需要新的治疗方法。多发性硬化症患者的中枢神经系统有一些区域似乎相对不受影响(神经纤维保留了被称为髓鞘的绝缘鞘)，而其他区域受到了损害(髓鞘丢失，损害了神经元的功能和健康)。这是一种动态的情况，身体不断修复损伤，但最终随着疾病的发展而失败。许多研究旨在加强髓鞘再生(修复髓鞘)，作为新的治疗干预的关键领域，从而保护神经元的健康和功能。然而，为了测试基于重新髓鞘形成的新疗法，必须使用实验室动物来模拟多发性硬化症，这些模型成本高昂，通常不能忠实地复制人类疾病的“斑块”性质，而且对治疗如何起作用的解释也有限。我们最近制作了一个更好的多发性硬化症实验室模型，它允许在培养皿中重现多发性硬化症的这种斑片状脱髓鞘性质，而不需要在这个过程中使用活动物。研究人员现在可以首次研究盘子中“健康”和“受损”组织之间的复杂相互作用。这一进步意味着，新的再髓鞘疗法可以更快、更有效地进行测试，更好地了解它们是如何工作的，并大大减少所需动物的数量。以前，一只活的成年动物只能对其神经系统的一个区域(即大脑或脊髓)给出一个实验结果，而我们的新模型使用在培养皿中培养的安乐死新生小鼠大脑或脊髓的切片，并分别进行分析。这为研究人员提供了6个脑片和10个脊髓片--所有这些都来自一只动物。在一个单一的治疗测试中，将使用100只实验室动物，现在可以替代使用几个动物的组织，另外一个好处是更好地了解这种疗法是如何起作用的。同样值得一提的是，以前实验动物可能不得不经历造成多发性硬化症的干预过程中的痛苦，而我们开发的这种新模型不会对活体动物进行干预，从而取代了对活体动物的使用。在看到这种模型在增加科学价值和减少动物使用方面的力量后，我们现在热衷于将这些技能和知识转移到其他研究小组，他们都是贝尔法斯特女王大学的独立研究小组的负责人，他们与我们接洽，希望在他们的实验室使用这个模型。这笔赠款有三个目标。首先，资助一名研究人员将与新的MS模型相关的技能和知识带到贝尔法斯特的实验室。主要目的是通过用我们的新模型取代他们现有的活体动物模型，减少他们研究中所需的动物数量。其次，我们的目标是通过在网上免费提供培训视频和详细的方案，鼓励在英国、欧洲和其他地方广泛采用这种模式，从而以较少的动物使用量带来更好的多发性硬化症研究能力。最后，我们将优化制造这种新的MS模型所需的材料的生产，以便它能够以简单、成本效益高和可重复的方式轻松地推广到大量实验室。我们预计，这种新的多发性硬化症模型将给研究人员带来直接和切实的好处，这将是推动他们采用它的主要吸引力。这些包括降低成本(活体动物实验成本很高)，同时在多个神经系统区域工作的能力，以及更好地了解治疗是如何起作用的。需要这笔赠款来催化和推动这种采用，传播这种模式所需的知识和方案，减少全球范围内的动物使用。